Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660

Article  PubMed  CAS  Google Scholar 

Prati R, Apple SK, He J, Gornbein JA, Chang HR (2005) Histopathologic characteristics Predicting HER-2/neu amplification in breast Cancer. Breast J 11(6):433–439

Article  PubMed  CAS  Google Scholar 

Altundag K, Bondy ML, Mirza NQ, Kau S-W, Broglio K, Hortobagyi GN, Rivera E (2007) Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis. Cancer 110(12):2640–2647

Article  PubMed  CAS  Google Scholar 

Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F, Peintinger F, Hanrahan EO, Sahin A, Guray M, Larsimont D, Feoli F, Stranzl H, Buchholz TA, Valero V, Theriault R, Piccart-Gebhart M, Ravdin PM, Berry DA, Hortobagyi GN (2009) High risk of recurrence for patients with breast Cancer who have human epidermal growth factor receptor 2–Positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27(34):5700–5706

Article  PubMed  PubMed Central  Google Scholar 

Goyette M-A, Duhamel S, Aubert L, Pelletier A, Savage P, Thibault M-P, Johnson RM, Carmeliet P, Basik M, Gaboury L, Muller WJ, Park M, Roux PP, Gratton J-P, Côté J-F (2018) The receptor tyrosine kinase AXL is required at multiple steps of the Metastatic Cascade during HER2-Positive breast Cancer Progression. Cell Rep 23(5):1476–1490

Article  PubMed  CAS  Google Scholar 

Harper KL, Sosa MS, Entenberg D, Hosseini H, Cheung JF, Nobre R, Avivar-Valderas A, Nagi C, Girnius N, Davis RJ, Farias EF, Condeelis J, Klein CA, Aguirre-Ghiso JA (2016) Mechanism of early dissemination and metastasis in Her2 + mammary cancer. Nature 540(7634):588–592

Article  PubMed  PubMed Central  CAS  Google Scholar 

Xue B, Krishnamurthy K, Allred DC, Muthuswamy SK (2013) Loss of Par3 promotes breast cancer metastasis by compromising cell–cell cohesion. Nat Cell Biol 15(2):189–200

Article  PubMed  CAS  Google Scholar 

Oh D-Y, Bang Y-J (2020) HER2-targeted therapies — a role beyond breast cancer. Nat Rev Clin Oncol 17(1):33–48

Article  PubMed  CAS  Google Scholar 

Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Gokmen E, Bashford A, Ruiz Borrego M, Kim SB, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A (2017) Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(12):1688–1700. https://doi.org/10.1016/s1470-2045(17)30717-9

Article  PubMed  CAS  Google Scholar 

Truong TH, Ung PM-U, Palde PB, Paulsen CE, Schlessinger A, Carroll KS (2016) Molecular basis for Redox activation of epidermal growth factor receptor kinase. Cell Chem Biology 23:7

Article  Google Scholar 

Tsou H-R, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD, Michalak RS, Nilakantan R, Discafani C, Golas J, Rabindran SK, Shen R, Shi X, Wang Y-F, Upeslacis J, Wissner A (2005) Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor Receptor-2 kinase activity. J Med Chem 48(4):1107–1131

Article  PubMed  CAS  Google Scholar 

Fox DB, Garcia NMG, McKinney BJ, Lupo R, Noteware LC, Newcomb R, Liu J, Locasale JW, Hirschey MD, Alvarez JV (2020) NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism. Nat Metab 2(4):318–334

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sies H, Berndt C, Jones DP (2017) Oxidative stress. Annu Rev Biochem 86:715–748. https://doi.org/10.1146/annurev-biochem-061516-045037

Article  PubMed  CAS  Google Scholar 

Nagpal A, Redvers RP, Ling X, Ayton S, Fuentes M, Tavancheh E, Diala I, Lalani A, Loi S, David S, Anderson RL, Smith Y, Merino D, Denoyer D, Pouliot N (2019) Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2 + ve breast cancer metastasis. Breast Cancer Res 21(1):1–19

Article  CAS  Google Scholar 

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

Article  PubMed  PubMed Central  CAS  Google Scholar 

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156(1–2):317–331. https://doi.org/10.1016/j.cell.2013.12.010

Article  PubMed  PubMed Central  CAS  Google Scholar 

Chen P, Chen F, Zhou B (2019) Risk of gastrointestinal events during neratinib therapy in patients with cancer: a systematic review and meta-analysis of clinical trials. Int J Clin Exp Med 12(4):3546–3557

CAS  Google Scholar 

Abbas R, Hug BA, Leister C, Sonnichsen D (2012) A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor. Cancer Chemother Pharmacol 70(1):191–199. https://doi.org/10.1007/s00280-012-1857-3

Article  PubMed  CAS  Google Scholar 

Chan A, Ruiz-Borrego M, Marx G, Chien AJ, Rugo HS, Brufsky A, Thirlwell M, Trudeau M, Bose R, García-Sáenz J, Egle D, Pistilli B, Wassermann J, Cheong K, Schnappauf B, Semsek D, Singer CF, Foruzan N, DiPrimeo D, McCulloch L, Hurvitz SA, Barcenas CH (2023) Final findings from the CONTROL trial: strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast. Cancer Breast 67:94–101

PubMed  Google Scholar 

Secombe KR, Ball IA, Shirren J, Wignall AD, Keefe DM, Bowen JM (2021) Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant. Breast Cancer 28(1):99–109. https://doi.org/10.1007/s12282-020-01133-9

Article  PubMed  Google Scholar 

Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Jänne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell C, Burris HA (2009) A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res 15(7):2552–2558. https://doi.org/10.1158/1078-0432.Ccr-08-1978

Article  PubMed  CAS  Google Scholar 

Abud HE, Chan WH, Jardé T (2021) Source and impact of the EGF family of ligands on intestinal stem cells. Front Cell Dev Biology 9:1–9

Article  Google Scholar 

Yamaoka T, Yan F, Cao H, Hobbs SS, Dise RS, Tong W, Polk DB (2008) Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis. Proc Natl Acad Sci USA 105(33):11772–11777

Article  PubMed  PubMed Central  CAS  Google Scholar 

Xiang J, Bandura J, Zhang P, Jin Y, Reuter H, Edgar BA (2017) EGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration. Nat Communication 8:1–13

Article  CAS  Google Scholar 

Yang Y-P, Ma H, Starchenko A, Huh WJ, Li W, Hickman FE, Zhang Q, Franklin JL, Mortlock DP, Fuhrmann S, Carter BD, Ihrie RA, Coffey RJ (2017) A chimeric egfr protein reporter mouse reveals Egfr localization and trafficking in vivo. Cell Rep 19(6):1257–1267

Article  PubMed  PubMed Central  CAS  Google Scholar 

Hirsh V, Blais N, Burkes R, Verma S, Croitoru K (2014) Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors. Curr Oncol 21(6):329–336. https://doi.org/10.3747/co.21.2241

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sandhu BK, Tripp JH, Candy DC, Harries JT (1981) Loperamide: studies on its mechanism of action. Gut 22(8):658–662. https://doi.org/10.1136/gut.22.8.658

Article  PubMed  PubMed Central  CAS  Google Scholar 

Pannemans J, Corsetti M (2018) Opioid receptors in the G